Are You Confident of the Diagnosis?

What you should be alert for in the history

Patients with multicentric reticulohistiocytosis (MRH) usually present with a cutaneous and mucosal eruption with severe arthritis. Severe chronic diffuse polyarthritis with arthralgias is the initial sign of the disease in two-thirds of patients. Patients may complain of weight loss, fever, and weakness. The disease primarily affects Caucasian adults, especially women in the fourth decade. Pediatric cases are rare. Patients often experience remission in their disease in 5-10 years with persisting joint deformities.

Characteristic findings on physical examination

The typical cutaneous lesions of MRH are multiple papules and nodules, ranging in size from a few millimeters to 2 centimeters in diameter with a reddish, brown, or yellowish coloration. Acral distribution is common with particular involvement of the head, ears, hands, fingers (Figure 1).

Figure 1.

Erythematous papules involving the fingers with periungual involvement which is common in MRH. Note deformity of DIP joint. (Courtesy of Cutis. 2010;85:153-55. 2010, Quadrant HealthCom Inc.)

Periarticular nodules may develop, mimicking rheumatoid nodules. Periungual papules around the nail folds described as ’coral beads’ is characteristic of the disorder and may be noted in approximately 40% of cases. This can be associated with brittleness, longitudinal ridging, and atrophy of the nails.

Some patients will develop multiple small papules scattered over the trunk. Occasionally, patients report pruritus, but the lesions are usually asymptomatic and do not ulcerate. Cartilaginous destruction of the nose and ears has been reported. A photodistribution pattern of the eruption along with poikiloderma can suggest underlying collagen vascular disease, especially dermatomyositis.

Reports of patients manifesting leonine facies may be difficult to distinguish from scleromyxedema. Approximately 50% of patients develop mucous membrane lesions which can involve the oral pharyngeal and nasal mucosa. A chronic diffuse polyarthritis is often detected on physical exam. Shortening and telescoping of involved fingers may produce an ’opera glass’ deformity of the fingers.

Expected results of diagnostic studies

Skin biopsies of cutaneous lesions of MRH demonstrate a dermal infiltrate of lymphocytes and histiocytes with occasional plasma cells and eosinophils. The histiocytes have a characteristic appearance with both mononuclear and multinuclear cells and abundant homogeneous, eosinophilic, and finely granular cytoplasm.

The characteristic x-ray findings of the joints include rapidly progressive erosions that spread from the margins to the joint surfaces. Well-circumscribed marginal erosions with juxarticular reabsorption is often described as ’widening of the joint space’. On laboratory evaluation, an elevated ESR and anemia is seen in over 50% of patients and one-third has elevated cholesterol. The rheumatoid factor is negative.

Diagnosis confirmation

MRH needs to be differentiated from other histiocytoses. Juvenile xanthogranuloma usually has an early age of onset, unlike MRH and lacks significant joint involvement. Patients with MRH that exhibit poikilodermatous findings and photosensitivity must be differentiated from dermatomyositis, but cutaneous histology helps differentiate the diagnosis.

Patients with MRH who demonstrate significant arthritis and juxta-articular nodules can be confused with rheumatoid arthritis, but they are rheumatoid factor negative. Some patients with MRH may develop leonine facies and widespread papular lesions on the trunk, which can suggest the diagnosis of scleromyxedema, but this diagnosis is excluded by cutaneous histology.

Who is at Risk for Developing this Disease?

MRH affects primarily adults, especially women in their forties. Pediatric cases are rare. Many patients with MRH have been reported to have a positive PPD, but organisms of tuberculosis are not noted on skin biopsy specimens.

What is the Cause of the Disease?

Pathophysiology

The pathogenesis of the disease is unknown. MRH may represent an abnormal histiocytic response to various stimuli. Mycobacteria have been suggested as a possible trigger due to an increased incidence of positive tuberculin skin tests in these patients, but no mycobacteria have been identified in the skin lesions. An underlying autoimmune or possible neoplastic disorder has also been speculated.

Systemic Implications and Complications

Multicentric reticulohistiocytosis is a systemic disease and can affect nearly every organ.

Cardiopulmonary involvement can produce pericarditis, pleuritis, and pulmonary infiltrates. The muscles can be affected, manifesting as myositis and myoatrophy. Involvement of the eyes can produce ocular complications, including exophthalmos and conjunctival infiltration. The thyroid gland, salivary glands, gastrointestinal tract, kidneys, and bone marrow can also be involved.

A symmetric inflammatory polyarthritis can affect the synovial tissues, including the hands, wrists, fingers, shoulders, elbows, hips, ankles, feet, and spine. The arthritis can be rapidly progressive and destructive. Severe involvement of the interphalangeal joints causes shortening and telescoping of the involved fingers, producing an ’opera glass’ hand deformity. Arthritis mutilans can occur in 30-50% of cases. After 6-8 years, the arthritis often goes into remission, but joint deformities persist.

An associated malignant neoplasm can be identified in 20-30% of cases. It is not considered a true paraneoplastic disorder because it does not parallel the course of the associated malignant neoplasm and no specific malignant neoplasm has been identified. Solid tumors most frequently reported include bronchial, breast, gastric, and cervical carcinomas. There are also reports of lymphoma and malignant melanoma.

Approximately half of patients with MRH may has an elevated sedimentation rate and anemia. One-third have hypercholesterolemia. Many patients have a positive tuberculin skin test. The disorder has been reported with systemic vasculitis, autoimmune disease, and tuberous sclerosis.

Patients diagnosed with MRH should be evaluated for an underlying malignancy. All patients should have a chest x-ray and be evaluated for blood in their stool.

Women should have a breast exam and mammogram, along with a PAP smear. Due to the increased incidence of gastrointestinal malignancies, endoscopy and colonoscopy should be considered, based on history and physical exam. A prostate exam and urinalysis are important for men.

A referral to rheumatology should be considered to evaluate for an inflammatory polyarthritis and evidence of muscle involvement. Screening for cardiopulmonary and thyroid involvement by an internist and ocular involvement by an ophthalmologist is important. Patients should have a CBC, erythrocyte sedimentation rate, lipid profile, and a tuberculin skin test performed.

Treatment Options

Medical options

Methotrexate

Prednisone

TNF inhibition

Cyclophosphamide

Chlorambucil

Bisphosphonates

Azathoioprine

NSAIDS

Surgical options

Surgical excision of large symptomatic nodules

Other options

Physical therapy for arthritis

Optimal Therapeutic Approach for this Disease

There is no consistently effective treatment for MRH. Determining efficacy of therapy is difficult, due to the rarity of the disease, intermittent fluctuatations in severity, and tendency toward spontaneous remission after 6-8 years. The prognosis of the disease is determined by the severity of the osteoarticular disease, presence of an underlying malignancy, and associated visceral involvement. Therapy should be targeted at improving cutaneous disease and minimizing joint symptoms and joint destruction.

Lian and Granston first proposed sequentional combination therapy with systemic steroids, methotrexate, and cyclophosphamide in 1996. Since that time, there has been a tendency toward combination therapy with systemic steroids, methotrexate, and tumor necrosis factor alpha inhibition. Chlorambucil, azathioprine, hydroxychloroquine, leflunomide, cyclosporine, and nonsteroidal anti-inflammatory drugs have also been reported to provide varying degrees of benefit.

MRH is best managed with combination therapy to improve efficacy and decrease risk of side-effects. Monotherapy usually not beneficial as initial treatment. The combination of methotrexate and prednisone provides initial therapeutic benefit for skin and joints.

Oral methotrexate is started at 7.5mg weekly and gradually increased to 15-25mg weekly as tolerated with careful laboratory monitoring. At the same time, prednisone is initiated at 0.5-1.0mg/kg daily and maintained at this dose for 4 weeks, then gradually tapered over 4 months. Prednisone does not induce complete remission, but provides symptomatic improvement in 2-4 weeks.

The response to this combination therapy is highly variable and unpredictable with the skin and joints often responding to different degrees. At 4-6 months, the addition of a tumor necrosis factor alpha inhibitor could be considered, if the skin or joints are not responding adequately. The rationale for using TNF blockers follows the discovery of over secretion of TNF alpha by synovial cells of patients with MRH.

Significant improvement in the skin and joint manifestations of psoriasis patients with documented elevated levels of TNF have occurred with TNF blockers. Etanercept, infliximab, and adalimumab have been reported to be beneficial. There is disparity in the literature in response to TNF blockers. Patients failing to respond to etanercept may improve with infliximab and dose escalation of the TNF blocker may be necessary, as in psoriasis therapy.

Patients who fail to respond to prednisone, methotrexate, and TNF blockers can be treated with cyclophosphamide. The prednisone can be continued while the TNF blocker and methotrexate are discontinued. Cyclophosphamide can be initiated at low dose levels 0.5-1.0mg/kg daily or higher levels 1.0- 2.0mg/kg daily, if the disease is more severe. Cyclophosphamide is reserved for more resistant cases, due to potential side effects of bone marrow suppression, hemorrhagic cystitis, and increased risk of transitional cell bladder cancer.

If patients do not tolerate cyclosphosphamide, chlorambucil could be substituted at 0.03 - 0.3mg/kg daily. Chlorambucil can increase the risk of developing non-Hodgkin’s B-cell lymphoma and acute leukemia, along with bone marrow suppression. Because of the significant pre-existing association of MRH with malignancy, the use of these cytotoxic agents requires that physicians outline the risk and benefits with their patients prior to initiating therapy.

The addition of bisphosphonates, along with systemic steroids and methotrexate, is another potential therapeutic approach. MRH synovial fluid contains numerous macrophages that are capable of differentiating into osteoclasts by the RANKL (receptor activator for nuclear factor Kappa B ligand) assay.

Pamidronate treatment of a patient with MRH resulted in less osteoclast formation and lacunar resorption. Inhibitors of osteoclast formation and resorption may be beneficial in preventing severe joint destruction in MRH. Bisphosphonates like alendronate and zoledronate have been shown to improve both arthritis and skin lesions.

The role of other agents in the treatment of MRH is unclear, due to the limited number of case reports. Azathioprine, hydroxychloroquine, cyclosporine, leflunomide, and nonsteroidal anti-inflammatory drugs could be considered as components of combination therapeutic regimens with systemic steroids.

In general, the response rate of the cutaneous and joint manifestation of MRH to combination therapy, which includes methotrexate and prednisone, is highly variable. Although the joint symptoms gradually improve over several months, destructive changes of the joints are often permanent. The cutaneous lesions often take 3-6 months to improve.

Patient Management

Prior to initiating therapy, it must be considered that approximately 25% of patients with MRH have or will develop an underlying malignancy. It is important to perform a thorough age and gender appropriate malignancy screening prior to initiating therapy.

Many patients have a history of a positive PPD and screening for active tuberculosis prior to treatment is important. It is also important to remember that malignancies often occur after the initial diagnosis of MRH. A constant vigilance for an underlying malignancy is important throughout therapy.

It is reasonable to initiate prednisone and methotrexate therapy and monitor the clinical response for 2-6 months prior to adding TNF alpha inhibitors or cytotoxic therapy. Patients on prednisone therapy need to be monitored for cataracts, osteoporosis, hypertension, and elevated blood glucose.

Appropriate vaccinations should be administered in advance and patients should be started on vitamin D and calcium supplementation. Methotrexate therapy requires following appropriate guidelines of care, including monitoring renal functions, hepatic function, CBC, and watching for potential drug interactions.

The addition of TNF blockers should be used with caution due to case reports of patients with positive PPDs. A quantiferon gold assay can be obtained if the patient has a positive PPD but no clinical evidence of TB. If the quantiferon gold test is positive, the patient should be treated for TB before use of a TNF inhibitor; and if negative, there is no concern.

A baseline and yearly PPD should be performed. Patients on cyclophosphamide need to be monitored for bone marrow toxicity, hemorrhagic cystitis, development of bladder cancer, and induction of other malignancies. Patients on cyclophosphamide should drink plenty of fluids and void frequently to decrease risk of hemorrhagic cystitis. Patients treated with chlorambucil require careful surveillance for bone marrow toxicity and induction of leukemia and squamous cell cancer.

The addition of bisphosphonates for MRH requires monitoring for hypocalcemia and osteonecrosis, primarily of the jaw. Esophagitis and esophageal and gastric ulceration can occur with oral agents.

It is always important to inform patients that there is no proven effective treatment for MRH and response to therapy is unpredictable. Patients with MRH need to be aware of their increased risk of developing a malignancy due to their disease and that some therapies hypothetically could increase this risk.

Although patients may develop improvement in their joint symptoms, therapy may not prevent destructive joint disease. The use of systemic medications has a significant risk of potentially life-threatening complications and will need to be carefully monitored.

Unusual Clinical Scenarios to Consider in Patient Management

Important clinical situations may arise in the management of patients with MRH. A significant number of patients have been found to have a positive PPD, but no active tuberculosis. These patients may require an infectious disease consultation and INH (isoniazide) prior to therapy with immunosuppressive agents. Patients may be diagnosed with a malignancy prior to or during therapy. This will require collaborating care with an oncologist and potentially modifying therapy based on the malignancy.

Although unpredictable, surgical removal of an underlying malignancy has been reported to sometimes significantly improve MRH. It is important to remember that MRH can affect organs other than the skin, mucous membranes, and joints.

A worsening of cardiac function, pulmonary function, muscle strength, or visual acuity may be a direct result of MRH affecting internal organs. This may require collaborative care with internal medicine specialists and ophthalmology.

Joint involvement is one of the most disturbing and disabling aspects of this disease. Co-management with rheumatology is critical in maintaining joint function and minimizing permanent joint destruction.

(This is a case report and review of the literature of patients with MRH developing complete or near-complete remissions with different therapeutic approaches. They propose a regimen of oral methotrexate 7.5mg weekly, gradually increased to 15-25mg weekly as tolerated and prednisone 0.5-1.0mg/kg daily. The prednisone is gradually tapered over 3-4 months. If patients are methotrexate intolerant or fail to respond to the above regimen, cyclophosphamide (1.0-2.0mg/kg daily) or low-dose cyclophosphamide (0.5-1.0mg/kg daily) is added. If cyclophosphamide is not tolerated, chlorambucil (0.03-0.3mg/kg daily) is an alternative.)

(This article demonstrated significant cutaneous and articular improvement with etanercept in a patient with MRH who failed to have an adequate response to prednisone, methotrexate, cyclophosphamide, and chlorambucil. Etanercept allowed tapering of prednisone and methotrexate.)

(A case report of a patient with severe cutaneous and articular manifestations of MRH who failed to adequately respond to methotrexate, prednisone, chlorambucil, cyclophosphamide, and hydroxychloroquine, who significantly improved with the addition of etanercept 25mg biweekly. There was some progression of articular deformities despite control of synovitis.)

(A patient with MRH who failed significant improvement on prednisone, methotrexate, and etanercept 50mg weekly, demonstrated a significant response when etanercept was switched to infliximab. Infliximab was initiated at 5mg/kg infusions at weeks 0, 2, and 6 and then every 8 weeks. Monoclonal TNF-alpha inhibitors may be more effective than TNF-alpha receptor inhibitors in selected cases.)

(This article is a case report of a patient with MRH who had clinical improvement in skin and joint disease after one month with alendronate. Alendronate was given 10mg intravenously weekly for 6 weeks and then monthly. Remission was maintained for more than 2 years. Alendronate may act directly on monocyte/macrophage infiltrates in the skin and synovium.)

(Synovial fluid in a patient with MRH was demonstrated to contain mononuclear cells that promote development of osteoclasts. MRH synovial fluid also contained increased tumor necrosis factor alpha. Pamidronate treatment reduced the number of synovial fluid macrophages and resulted in less osteoclast formation and lacunar resorption.)